U.S. patent application number 15/513526 was filed with the patent office on 2017-10-19 for bondable microcapsules and surface functionalized fillers.
The applicant listed for this patent is PREMIER DENTAL PRODUCTS COMPANY. Invention is credited to Stephen M. GROSS, Mark A. LATTA, William A. MCHALE.
Application Number | 20170296440 15/513526 |
Document ID | / |
Family ID | 55582000 |
Filed Date | 2017-10-19 |
United States Patent
Application |
20170296440 |
Kind Code |
A1 |
GROSS; Stephen M. ; et
al. |
October 19, 2017 |
Bondable Microcapsules And Surface Functionalized Fillers
Abstract
A composition comprising microcapsules functionalized with
polymerizable functional groups on the surface of said
microcapsules wherein the functional groups form covalent bonds
with monomers in the continuous phase to enhance the mechanical
properties of the composition.
Inventors: |
GROSS; Stephen M.; (Omaha,
NE) ; MCHALE; William A.; (Collegeville, PA) ;
LATTA; Mark A.; (Omaha, NE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PREMIER DENTAL PRODUCTS COMPANY |
Plymouth Meeting |
PA |
US |
|
|
Family ID: |
55582000 |
Appl. No.: |
15/513526 |
Filed: |
September 24, 2015 |
PCT Filed: |
September 24, 2015 |
PCT NO: |
PCT/US2015/051931 |
371 Date: |
March 22, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62055127 |
Sep 25, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08G 18/8175 20130101;
A61K 6/62 20200101; B01J 13/16 20130101; A61K 6/887 20200101; C08F
290/067 20130101; C08G 18/3203 20130101; A61K 31/14 20130101; A61K
6/72 20200101; A61K 6/893 20200101; C01B 9/08 20130101; C08G 18/672
20130101; C08G 18/72 20130101; A61K 6/74 20200101; A61K 31/4425
20130101; A61K 6/896 20200101; A61P 1/02 20180101; A61K 33/18
20130101; A61K 6/77 20200101; A61K 6/69 20200101 |
International
Class: |
A61K 6/083 20060101
A61K006/083; C08F 290/06 20060101 C08F290/06; B01J 13/16 20060101
B01J013/16; A61K 6/093 20060101 A61K006/093; A61K 6/09 20060101
A61K006/09; A61K 6/00 20060101 A61K006/00; A61K 6/00 20060101
A61K006/00; A61K 6/00 20060101 A61K006/00; A61K 6/00 20060101
A61K006/00; C08G 18/81 20060101 C08G018/81; A61K 6/00 20060101
A61K006/00 |
Claims
1. A composition comprising of monomer, initiator, and a
non-biodegradable microcapsule encapsulating an aqueous solution of
a salt, wherein said microcapsule has a surface functionalized with
a polymerizable functional group capable of polymerizing with said
monomer.
2. The composition of claim 1 where the aqueous solution of a salt
contains ions selected from the group consisting of: fluoride,
calcium, phosphate, and combinations thereof
3. The composition of claim 1 comprising a combination of salt
ions, wherein the combination of salt ions is achieved by using a
plurality of microcapsules that contain either fluoride, or
calcium, or phosphate, wherein each microcapsule contains only one
of the fluoride, calcium, or phosphate ions.
4. The composition of claim 1 where the aqueous solution of a salt
contains benzalkonium or cetylpyridinium ions.
5. The composition of claim 1 where the aqueous solution of a salt
is specifically a combination of salts that result in a buffer
solution.
6. The composition of claim 5 where the buffered solution contains
a therapeutic agent.
7. The composition of claim 1 further comprising a
photoinitiator.
8. The composition of claim 1 wherein the functional group is an
acrylate group.
9. A composition comprising of a polymeric continuous phase and a
discontinuous phase, wherein the continuous phase comprises a
polymeric material and the discontinuous phase a microcapsule
encapsulating an aqueous solution, wherein said microcapsule has a
surface functionalized with a polymerizable functional group and is
bonded to the polymeric continuous phase.
10. The composition of claim 9 where the aqueous solution is an
aqueous solution of a salt that contains ions selected from the
group consisting of: fluoride, calcium, phosphate, and combinations
thereof
11. The composition of claim 9 where the aqueous solution is an
aqueous buffered therapeutic solution comprising benzalkonium or
cetylpyridinium ions or combinations thereof
12. The composition of claim 9 comprising a plurality of
microcapsules that contain either a fluoride, calcium, phosphate,
benzalkonium, cetylpyridinium, or iodide ions, wherein each
microcapsules contains only one of the ions.
13. A composition comprising a continuous phase comprising a
monomer, and a discontinuous phase comprising at least one filler
comprising a microcapsule encapsulating a fluid, and an initiator,
wherein said microcapsule has a surface functionalized with a
polymerizable functional group capable of polymerizing with said
monomer.
14. The composition of claim 13 wherein said fluid is a salt
solution selected from the group consisting of: calcium, fluoride,
and phosphate, and combinations thereof
15. The composition of claim 13 wherein said fluid is selected from
the group consisting of: benzalkonium, cetylpyridinium, and iodide,
and combinations thereof
16. The composition of claim 13 wherein said fluid is a silicone or
rubber based material.
17. The composition of claim 13 wherein said functional group is an
acrylate group.
18. The composition of claim 13 comprising a plurality of
microcapsules, wherein the fluid within said microcapsules contains
either fluoride, calcium, phosphate, benzalkonium, iodide, or
cetylpyridinium ions, and wherein each microcapsule contains only
type of ion.
19. A composition comprising of a polymeric continuous phase, an
initiator, and a microcapsule encapsulating a fluid, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer.
20. The composition of claim 19 wherein said microcapsule has a
surface functionalized with a polymerizable functional group that
is covalently bonded to the continuous phase.
21. The composition of claim 19 wherein the fluid comprises a salt
solution containing an ion selected from the group consisting of
calcium, fluoride, phosphate, benzalkonium, cetylpyridinium,
iodide, and combinations thereof
22. The composition of claim 19 wherein the fluid comprises a
combination of salts that result in a buffer solution.
23. The composition of claim 19 wherein the microcapsule
encapsulates a silicone.
24. The silicone of claim 23 having a molecular weight between
about 12,500 and 2,500,000 g/mol.
25. The composition of claim 19 wherein the microcapsule is
encapsulating a rubber material.
26. The composition of claim 19 further comprising a glass
filler.
27. The composition of claim 19 further comprising an
inhibitor.
28. A composition comprising of a first monomer, an initiator, and
a microcapsule encapsulating a second monomer, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with the first monomer or
second monomer.
29. A composition comprising a monomer and a photoinitiator in the
continuous phase and a microcapsule and an inhibitor in the
discontinuous phase, wherein the microcapsule has a surface
functionalized with a polymerizable acrylate group capable of
covalently bonding to the continuous phase.
30. A composition comprising a polymeric continuous phase having a
non-biodegradable microcapsule covalently bonded to said polymeric
continuous phase, wherein said polymeric continuous phase is
created by a composition comprising a monomer and a photoinitiator
in the continuous phase and a microcapsule and an inhibitor in the
discontinuous phase, wherein the microcapsule has a surface
functionalized with a polymerizable acrylate group capable of
covalently bonding to the continuous phase, and wherein a light
source activates the photoinitiator which allows the monomers in
the continuous phase to polymerize and bind with the acrylate group
on the microcapsule.
31. A composition comprising of a TEGMA and bisGMA monomers, an
initiator, and a microcapsule encapsulating an aqueous solution of
a salt selected from the group consisting of: benzalkonium,
cetylpyridinium, and iodide, and combinations thereof, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer, wherein
the microcapsule is between 2-5 w/w % of the composition and has
methacrylate functional groups on the surface, and wherein the
methacrylate group is capable of reacting with the methacrylate
groups of the monomers in the continuous phase.
32. A method for manufacturing a composition having a microcapsule
and a continuous phase, wherein said microcapsule comprises a
functionalized surface capable of covalently bonding to the
continuous phase comprising: mixing an oligomeric urethane by
reaction of a diol and diisocyanate, in which the diisocyanate is
used in molar excess, and reacting for a about 1 hour; adding
2-hydroxyethylmethacrylate to the resulting oligomeric urethane
mixture to terminate chain ends with methacrylate functional
groups; isolating the functionalized urethane; adding the isolated
functionalized urethane to an oil phase comprising an emulsifying
agent and an organic solvent wherein a surfactant free inverse
emulsion is formed with the addition of an aqueous phase that may
contain a salt; adding diol to the surfactant free reverse emulsion
to polymerize the urethane oligomers and encapsulate the aqueous
solution; and isolating the microcapsules by centrifugation.
Description
FIELD OF INVENTION
[0001] The present application is generally related to
compositions, methods and products useful for composite materials
comprising microcapsules. The compositions comprise microcapsules
with polymerizable functional groups added to monomeric or
polymeric continuous phases that enhance the mechanical properties
of the composite. Further, the microcapsules can be filled with
liquid phases that further improve the mechanical properties of the
composite, or render the composite bioactive for applications
including, but not limited to, promoting remineralization and
imparting antimicrobial activity to the composite.
BACKGROUND OF THE INVENTION
[0002] Dental composite materials are utilized in many cases to
fill caries and to improve tooth health. At one time, metal-based
amalgams, then porcelain or other ceramic materials were used in a
variety of remedial dental procedures. Now, synthetic composites
are used as practical alternatives to these materials for such
procedures. A composite is a polymer, otherwise referred to as a
resin, which has at least one additive. An additive can be anything
added to the polymer or resin to impart a desired property. The
composite generally starts out as a paste or liquid and begins to
harden when it is activated, either by adding a catalyst, adding
water or another solvent, or photoactivation. Advantageously,
synthetic composites provide an aesthetically more natural
appearance versus porcelain or other ceramic materials.
[0003] Synthetic composites are typically made from complex
mixtures of multiple components. Synthetic composites must be
completely dissolvable in a fluid vehicle, yet remain flowable and
viscous; undergo minimal thermal expansion during polymerization;
be biocompatible with surrounding surfaces of tooth enamel and
colloidal dentin; and, have aesthetic similarity to natural
dentition in terms of color tone and polishable texture.
Furthermore, the synthetic composite must have sufficient
mechanical strength and elasticity to withstand ordinary
compressive occlusive forces, without abnormal wearing and without
causing abrasion to dentinal surfaces.
[0004] The different varieties of synthetic composites may be
approximately divided into three main groups of products: synthetic
resin-based dental composites, glass-based dental composites, and
hybrid dental composites.
[0005] A synthetic resin-based dental composite typically comprises
several monomers combined together. A monomer is a chemical that
can be bound as part of a polymer. The synthetic resin-based dental
composite includes other materials, such as silicate glass or
processed ceramic that provides an essential durability to the
composite. These materials-may also be made from an inorganic
material, consisting of a single type or mixed variety of
particulate glass, quartz, or fused silica particles. Using
differing types of inorganic materials, with differing diameter
sizes or size mixtures, results in differing material
characteristics.
[0006] Glass-based dental composites are made from a glass
particles, such as powdered fluoroaluminosilicate, dissolved in an
aqueous polyalkenoate acid. An acid/base reaction occurs
spontaneously, causing precipitation of a metallic polyalkenoate,
which subsequently solidifies gradually. The glass particles may be
made from silicate, such as silicone dioxide or aluminum silicate,
but may also include an intermixture of barium, borosilicate,
alumina, aluminum/calcium, sodium fluoride, zirconium, or other
inorganic compounds. Some of the earlier glass-based composites
were formulated to contain primarily a mixture of acrylic acid and
itaconic acid co-monomers. However, more recently such hybrid
products are modified to include other polymerizable components,
such as HEMA or BisGMA.
[0007] Hybrid composites are the third category of synthetic dental
composites. Hybrid composites combine glass particles with one or
more polymers. Hybrid composites may comprise water-soluble
polymers other than polyalkenoate, such as hydroxyethyl
methacrylate (HEMA) and other co-polymerizing methacrylate-modified
polycarboxylic acids, which are catalyzed by photo activation.
Other hybrid composites may be modified to include polymerizable
tertiary amines, catalyzed by reaction with peroxides.
[0008] Synthetic dental composites are increasingly used more often
for dental procedures, such as restoration and repair. Restoration
and repair includes, for example, fillings, crowns, bridges,
dentures, orthodontic appliances, cements, posts and ancillary
parts for dental implants to name a few. Most common, synthetic
dental composites are used for anterior Class III and Class V
reconstructions, for smaller size Class I and Class II molar
reconstructions, for color-matching of cosmetic veneers, and for
cementing of crowns and overlays. Nonetheless certain disadvantages
of these materials have been noted. For example, the trace amounts
of unconverted monomers and/or catalyst that may remain within the
composite and, if subsequently absorbed systemically in humans, may
be potentially physiologically harmful.
[0009] Another major drawback associated with synthetic composites
is that they tend to wear more rapidly, especially when placed in
appositional contact with load-bearing dental surfaces, a
deficiency that often limits the purposeful use of such materials
primarily to repair of defects within anterior maxillary or readily
visible mandibular surfaces.
[0010] Perhaps the most significant disadvantage associated with
synthetic composites is that they have a comparatively lower
resistance to fracture. Even relatively minor surface
discontinuities within the composite, whether occurring from
injurious trauma or occlusive stress, may progressively widen and
expand, eventually resulting in partial or complete disintegration
of the reconstruction or repair. This greater susceptibility to
fracture is thought to be correlated with the dental reconstruction
or repair.
[0011] Fracture susceptibility is also correlated with the
proportional volume of the amount of synthetic composite required,
or the lesser fraction of intact enamel and dentinal tooth material
that remains available, prior to reconstruction or repair. It is
well established from studies of the "cracked tooth syndrome" that
once a damaging fracture has occurred, tooth loss may be almost
inevitable, especially for carious teeth that have been previously
filled. An improved synthetic composite having greater resistance
to fracture would be significantly advantageous.
[0012] The susceptibility of fracture and damage to bone tissue is
relevant to children and adults alike whom require filling of
caries in tooth materials. However, it is known that certain
changes in bone mass occur over the life span of an individual.
After about the age of 40 and continuing to the last stages of
life, slow bone loss occurs in both men and women. Loss of bone
mineral content can be caused by a variety of conditions, and may
result in significant medical problems. If the process of tissue
mineralization is not properly regulated, the result can be too
little of the mineral or too much--either of which can compromise
bone health, hardness and strength. A number of bone growth
disorders are known which cause an imbalance in the bone remodeling
cycle. Chief among these are metabolic bone diseases such as
osteoporosis, osteoplasia (osteomalacia), chronic renal failure and
hyperparathyroidism, which result in abnormal or excessive loss of
bone mass known as osteopenia. Other bone diseases, such as Paget's
disease, also cause excessive loss of bone mass at localized
sites.
[0013] Osteoporosis is a structural deterioration of the skeleton
caused by loss of bone mass resulting from an imbalance in bone
formation, bone resorption, or both. Bone resorption is the process
by which osteoclasts break down bone and release the minerals,
resulting in a transfer of calcium from bone fluid to the blood.
Bone resorption dominates the bone formation phase, thereby
reducing the weight-bearing capacity of the affected bone. In a
healthy adult, the rate at which bone is formed and resorbed is
tightly coordinated so as to maintain the renewal of skeletal bone.
However, in osteoporotic individuals, an imbalance in these bone
remodeling cycles develops which results in both loss of bone mass
and in formation of micro-architectural defects in the continuity
of the skeleton. These skeletal defects, created by perturbation in
the remodeling sequence, accumulate and finally reach a point at
which the structural integrity of the skeleton is severely
compromised and bone fracture is likely. Although this imbalance
occurs gradually in most individuals as they age, it is much more
severe and occurs at a rapid rate in postmenopausal women. In
addition, osteoporosis also may result from nutritional and
endocrine imbalances, hereditary disorders and a number of
malignant transformations.
[0014] Osteoporosis in humans is preceded by clinical osteopenia
(bone mineral density that is greater than one standard deviation
but less than 2.5 standard deviations below the mean value for
young adult bone), a condition found in approximately 25 million
people in the United States. Another 7-8 million patients in the
United States have been diagnosed with clinical osteoporosis
(defined as bone mineral content greater than 2.5 standard
deviations below that of mature young adult bone). Osteoporosis is
one of the most expensive diseases for the health care system,
costing billions of dollars annually in the United States. In
addition to health care related costs, long-term residential care
and lost working days add to the financial and social costs of this
disease. Worldwide, approximately 75 million people are at risk for
osteoporosis.
[0015] The frequency of osteoporosis in the human population
increases with age, and among Caucasians is predominant in women,
who comprise approximately 80% of the osteoporosis patient pool in
the United States. In addition in women, another phase of bone loss
occurs possibly due to postmenopausal estrogen deficiencies. During
this phase of bone loss, women can lose an additional 10% in the
cortical bone and 25% from the trabecular compartment. The
increased fragility and susceptibility to fracture of skeletal bone
in the aged is aggravated by the greater risk of accidental falls
in this population. More than 1.5 million osteoporosis-related bone
fractures are reported in the United States each year. Fractured
hips, wrists, and vertebrae are among the most common injuries
associated with osteoporosis. Hip fractures in particular are
extremely uncomfortable and expensive for the patient, and for
women correlate with high rates of mortality and morbidity.
[0016] Patients suffering from chronic renal (kidney) failure
almost universally suffer loss of skeletal bone mass, termed renal
osteodystrophy. While it is known that kidney malfunction causes a
calcium and phosphate imbalance in the blood, to date replenishment
of calcium and phosphate by dialysis does not significantly inhibit
osteodystrophy in patients suffering from chronic renal failure. In
adults, osteodystrophic symptoms often are a significant cause of
morbidity. In children, renal failure often results in a failure to
grow, due to the failure to maintain and/or to increase bone
mass.
[0017] Osteoplasia, also known as osteomalacia ("soft bones"), is a
defect in bone mineralization (e.g., incomplete mineralization),
and classically is related to vitamin D deficiency (1,25-dihydroxy
vitamin D3). The defect can cause compression fractures in bone,
and a decrease in bone mass, as well as extended zones of
hypertrophy and proliferative cartilage in place of bone tissue.
The deficiency may result from a nutritional deficiency (e.g.,
rickets in children), malabsorption of vitamin D or calcium, and/or
impaired metabolism of the vitamin.
[0018] Hyperparathyroidism (overproduction of the parathyroid
hormone) is known to cause malabsorption of calcium, leading to
abnormal bone loss. In children, hyperparathyroidism can inhibit
growth, in adults the skeleton integrity is compromised and
fracture of the ribs and vertebrae are characteristic. The
parathyroid hormone imbalance typically may result from thyroid
adenomas or gland hyperplasia, or may result from prolonged
pharmacological use of a steroid. Secondary hyperparathyroidism
also may result from renal osteodystrophy. In the early stages of
the disease, osteoclasts are stimulated to resorb bone in response
to the excess hormone present. As the disease progresses, the
trabecular bone ultimately is resorbed and marrow is replaced with
fibrosis, macrophages and areas of hemorrhage as a consequence of
microfractures, a condition is referred to clinically as osteitis
fibrosa.
[0019] Paget's disease (osteitis deformans) is a disorder currently
thought to have a viral etiology and is characterized by excessive
bone resorption at localized sites which flare and heal but which
ultimately are chronic and progressive, and may lead to malignant
transformation. The disease typically affects adults over the age
of 25.
[0020] Although osteoporosis has been defined as an increase in the
risk of fracture due to decreased bone mass, none of the presently
available treatments for skeletal disorders can substantially
increase the bone density of adults. A strong perception exists
among physicians that drugs are needed which could increase bone
density in adults, particularly in the bones of the wrist, spinal
column and hip that are at risk in osteopenia and osteoporosis.
[0021] Current strategies for the prevention of osteoporosis may
offer some benefit to individuals but cannot ensure resolution of
the disease. These strategies include moderating physical activity,
particularly in weight-bearing activities, with the onset of
advanced age, including adequate calcium in the diet, and avoiding
consumption of products containing alcohol or tobacco. For patients
presenting with clinical osteopenia or osteoporosis, all current
therapeutic drugs and strategies are directed to reducing further
loss of bone mass by inhibiting the process of bone absorption, a
natural component of the bone remodeling process that occurs
constitutively.
[0022] For example, estrogen is now being prescribed to retard bone
loss. There is, however, some controversy over whether there is any
long term benefit to patients and whether there is any effect at
all on patients over 75 years old. Moreover, use of estrogen is
believed to increase the risk of breast and endometrial cancer.
High doses of dietary calcium with or without vitamin D have also
been suggested for postmenopausal women. However, ingestion of high
doses of calcium can often have unpleasant gastrointestinal side
effects, and serum and urinary calcium levels must be continuously
monitored.
[0023] Other therapeutics which have been suggested include
calcitonin, bisphosphonates, anabolic steroids and sodium fluoride.
Such therapeutics however, have undesirable side effects, for
example, calcitonin and steroids may cause nausea and provoke an
immune reaction, bisphosphonates and sodium fluoride may inhibit
repair of fractures, even though bone density increases modestly,
which that may prevent their usage.
[0024] The above disorders are examples of conditions that may lead
to bone fractures, fissures or splintering of the bones in the
individuals who suffer from a given disorder. Current therapeutic
methods are insufficient to treat the disorders leaving a need for
improved treatments of bone fractures when they occur in the
individual. The present invention provides improved compositions,
products and methods for locally treating bone fractures, fissures,
splintering and similar breakages of the bone, or by strengthening
decomposed bone tissue by increasing the mechanism of
mineralization of the bone. It is conceivable that the current
invention also causes mineralization of the surrounding connective
tissue, such as collagen, cartilage, tendons, ligaments and other
dense connective tissue and reticular fibers.
The Oral Cavity
[0025] With respect to tissue decomposition in the oral cavity, it
is commonly known in the dental art that certain kinds of tooth
decomposition and decay that occurs over time in the mouth is
initiated by acid etching of the tooth enamel with the source of
the acid being a metabolite resulting from bacterial and enzymatic
action on food particles in the oral cavity. It is generally
understood that plaque, a soft accumulation on the tooth surface
consisting of an organized structure of microorganisms,
proteinaceous and carbohydrate substances, epithelial cells, and
food debris, is a contributory factor in the development of various
pathological conditions of the teeth and soft tissue of the oral
cavity. The saccharolytic organisms of the oral cavity which are
associated with the plaque, cause a demineralization or
decalcification of the tooth beneath the plaque matrix through
metabolic activity which results in the accumulation and localized
concentration of organic acids. The etching and demineralization of
the enamel may continue until they cause the formation of dental
caries and periodontal disease within the oral cavity.
[0026] Teeth are cycled through periods of mineral loss and repair
also as a result of pH fluctuations in the oral cavity. The overall
loss or gain of mineral at a given tooth location determine whether
the carious process will regress, stabilize or advance to an
irreversible state. Numerous interrelated patient factors affect
the balance between the remineralization and demineralization
portions of this cycle and include oral hygiene, diet, and the
quantity and quality of saliva. At the most extreme point in this
process, a restoration will be required to repair the tooth.
[0027] Methods for the prevention and reduction of plaque and tooth
decay within the oral cavity commonly involve the brushing of the
teeth using toothpastes; mechanical removal of the plaque with
dental floss; administration and rinsing of the oral cavity with
mouthwashes, dentifrices, and antiseptics; remineralization and
whitening of the teeth with fluoride agents, calcium agents and
whitening agents, and various other applications to the oral
cavity. Still missing in the field is a delivery system for the
remineralization of teeth that would address the challenges of
demineralization facing the teeth continually in the oral
cavity.
[0028] A tooth that has reached an advanced stage of decay often
requires installation of a dental restoration within the mouth.
Half of all dental restorations fail within 10 years, and replacing
them consumes 60% of the average dentist's practice time. Current
dental materials are challenged by the harsh mechanical and
chemical environment of the oral cavity with secondary decay being
the major cause of failure. Development of stronger and
longer-lasting biocompatible dental restorations by engineering
novel dental materials or new resin systems, enhancing existing
materials, and incorporating bioactive agents in materials to
combat microbial destruction and to sustain the harsh mechanical
and chemical environment of the oral cavity continues to be
desired.
[0029] Despite numerous preventive oral health strategies, dental
caries remains a significant oral health problem. More than 50% of
children aged 6-8 will have dental caries and over 80% of
adolescents over age 17 will have experienced the disease. Caries
is also seen in adults both as a primary disease and as recurrent
disease in already treated teeth. Advances in diagnosis and
treatment have led to non-invasive remineralizing techniques to
treat caries. However mechanical removal of diseased hard tissue
and restoration and replacement of enamel and dentin is still the
most widely employed clinical strategy for treating primary caries,
restoring function to the tooth and also blocking further decay. In
addition, nearly 50% of newly placed restorations are replacement
of failed restorations. Clearly, restorative materials are a key
component of treating this widespread disease.
[0030] The selection of a restorative material has significantly
changed in recent years. While dental amalgam is still considered a
cost effective material, there is a growing demand for tooth
colored alternatives that will provide the same clinical longevity
that is enjoyed by dental amalgam. The use of composite resins has
grown significantly internationally as a material of choice for
replacing amalgam as a restorative material for posterior
restorations. This demand is partially consumer driven by
preference for esthetic materials and the concerns regarding the
mercury content of amalgam. It is also driven by dentists
recognizing the promise of resin-based bonded materials in
preserving and even supporting tooth structure. Numerous studies
have suggested that bonding the restoration to the remaining tooth
structure decreases fracture of multi-surface permanent molar
preparations. Unfortunately, posterior teeth restored with direct
resin restorative materials have a higher incidence of secondary
caries. This has led to shorter clinical service and narrower
clinical indications for composite resin materials compared to
amalgam.
[0031] The most frequently cited reason for restoration replacement
is recurrent decay around or adjacent to an existing restoration.
It is likely that fracture at the margin due to polymerization
shrinkage can lead to a clinical environment at the interface
between a restoration and the tooth that collects dental plaque and
thus promotes decay. Therefore, developing dental materials with
anti-caries capability is a very high priority for extending the
longevity of restorations.
Tooth Remineralization
[0032] Although natural remineralization is always taking place in
the oral cavity, the level of activity varies according to
conditions in the mouth as discussed. Incorporation of fluoride
during the remineralization process has been a keystone for caries
prevention. The effectiveness of fluoride release from various
delivery platforms, including certain dental restorative materials
has been widely demonstrated. It is commonly accepted that caries
prevention from fluoride is derived from its incorporation as
fluorapatite or fluoride enriched hydroxyapatite in the tooth
mineral thereby decreasing the solubility of tooth enamel. More
recently, anti-caries activity has been demonstrated using the
strategy of increasing solution calcium and phosphate
concentrations to levels that exceed the ambient concentration in
oral fluids. In order for fluoride to be effective at
remineralizing previously demineralized enamel, a sufficient amount
of calcium and phosphate ions must be available. For every two (2)
fluoride ions, ten (10) calcium ions and six (6) phosphate ions are
required to form a cell of fluorapatite (Ca10(PO4)6F2). Thus the
limiting factor for net enamel remineralization is the availability
of calcium and fluoride in saliva.
[0033] The low solubility of calcium phosphates has limited their
use in clinical delivery platforms, especially when in the presence
of fluoride ions. These insoluble phosphates can only produce
available ions for diffusion into the enamel in an acidic
environment. They do not effectively localize to the tooth surface
and are difficult to apply in clinically usable forms. Because of
their intrinsic solubility, soluble calcium and phosphate ions can
only be used at very low concentrations. Thus they do not produce
concentration gradients that drive diffusion into the subsurface
enamel of the tooth. The solubility challenge is exacerbated by the
even lower solubility of calcium fluoride phosphates.
[0034] Several commercially available approaches exist using
calcium and phosphate preparations that have been commercialized
into various dental delivery models. These have been reportedly
compounded to overcome the limited bioavailability of calcium and
phosphate ions for the remineralization process. The first
technology uses casein phosphopeptide (CCP) stabilized with
amorphous calcium phosphate (ACP) (RECALDENT.RTM. CCP-ACP of
Cadbury Enterprises Pte. Ltd.). It is hypothesized that the casein
phosphopeptide can facilitate the stabilization of high
concentrations of ionically available calcium and phosphate even in
the presence of fluoride. This formulation binds to pellicle and
plaque and while the casein phosphopeptide prevents the formation
of dental calculus, the ions are available to diffuse down the
concentration gradient to subsurface enamel lesions facilitating
remineralization. As compared to the CCP-ACP, in the composition of
the invention, biologically available ions are available due to the
fact that the salts are already solvated in the microcapsule of the
invention. Amorphous calcium phosphate is not soluble in water or
saliva. Although the manufacturer claims release of bioavailable
ions from amorphous calcium phosphate, it is not as a result of the
dissolution of the complex. A second technology (ENAMELON.RTM.)
uses unstabilized amorphous calcium phosphate. Calcium ions and
phosphate ions are introduced as a dentifrice separately in a dual
chamber device forming amorphous calcium phosphate in-situ. It is
proposed that formation of the amorphous complex promotes
remineralization. A third approach uses a so-called bioactive glass
(NOVAMIN.RTM. of NovaMin Technology Inc.) containing calcium sodium
phosphosilicate. It is proposed that the glass releases calcium and
phosphate ions that are available to promote remineralization. More
recently dental composite formulations have been compounded using
zirconia-hybridized ACP that may have the potential for
facilitating clinical remineralization.
[0035] While the Recaldent.RTM. and Enamelon.RTM. preparations have
both in-situ and in-vivo evidence suggesting enhanced
remineralization, these are topically applied and do not
specifically target the most at risk location for recurrent caries
at the tooth restoration interface. While the bioactive glass and
the zirconia-hybridized-ACP filler technologies have potential,
they are relatively inflexible in terms of the range of
formulations in which they might be used due to the challenges of
dealing with brittle fillers and some of the limitations on
controlling filler particle size.
[0036] Another approach taken to decrease caries in the oral cavity
is the limiting of demineralization of enamel and bone by drinking
water fluoridation. It has been shown that the fluoride contained
in drinking water incorporates to some extent into hydroxyapatite,
the major inorganic component of enamel and bone. Fluoridated
hydroxyapatite is less susceptible to demineralization by acids and
is thus seen to resist the degradation forces of acidic plaque and
pocket metabolites. In addition, fluoride ion concentration in
saliva is increased through consumption of fluoridated drinking
water. Saliva thus serves as an additional fluoride ion reservoir
and in combination with buffering salts naturally found in salivary
fluid, fluoride ions are actively exchanged on the enamel surface,
further offsetting the effects of demineralizing acid
metabolites.
[0037] Notwithstanding the established benefits of fluoride
treatment of teeth, fluoride ion treatment can result in irregular
spotting or blotching of the teeth depending on the individual,
whether administered through drinking water or by topically applied
fluoride treatment. This effect is known to be both concentration
related and patient specific. In addition, the toxicology of
fluoride is being studied as to its long term effect on human
health. Desired is a targeted approach of fluoridation in the oral
cavity.
[0038] Another approach to limiting the proliferation of microflora
in the oral environment is through topical or systematic
application of broad-spectrum antibacterial compounds. Reducing the
number of oral microflora in the mouth results in a direct
reduction or elimination of plaque and pocket accumulation together
with their damaging acidic metabolite production. The major
drawback to this particular approach is that a wide variety of
benign or beneficial strains of bacteria are found in the oral
environment which may be killed by the same antibacterial compounds
in the same manner as the harmful strains. In addition, treatment
with antibacterial compounds may select for certain bacterial and
fungi, which may then become resistant to the antibacterial
compound administered and thus proliferate, unrestrained by the
symbiotic forces of a properly balanced microflora population. Thus
the application or administration of broad-spectrum antibiotics
alone is ill-advised for the treatment of caries and a more
specific, targeted approach is desired.
Tooth Whitening
[0039] Cosmetic dental whitening or bleaching has become extremely
desirable to the general public. Many individuals desire a "bright"
smile and white teeth, and consider dull and stained teeth
cosmetically unattractive. Unfortunately, without preventive or
remedial measures, stained teeth are almost inevitable due to the
absorbent nature of dental material. Everyday activities such as
eating, chewing, or drinking certain foods and beverages (in
particular coffee, tea, and red wine) and smoking or other oral use
of tobacco products cause undesirable staining of surfaces of
teeth. Extrinsic staining of the acquired pellicle arises as a
result of compounds such as tannins and polyphenolic compounds
which become trapped in and tightly bound to the proteinaceous
layer on the surfaces of teeth. This type of staining can usually
be removed by mechanical methods of tooth cleaning. In contrast,
intrinsic staining occurs when staining compounds penetrate the
enamel and even the dentin or arise from sources within the tooth.
The chromogens or color causing substances in these materials
become part of the pellicle layer and can permeate the enamel
layer. Even with regular brushing and flossing, years of chromogen
accumulation can impart noticeable tooth discoloration. Intrinsic
staining can also result from microbial activity, including that
associated with dental plaque. This type of staining is not
amenable to mechanical methods of tooth cleaning and chemical
methods are required.
[0040] Without specifically defining the mechanism of action of the
present invention, the compositions, products and methods of the
present invention enable the precipitation of salts onto the
surfaces of the teeth in the oral cavity and make the salts
available for adherence to the tooth surface and remineralization
of the teeth. The mineralizing salts are deposited in the
interstitial spaces of the teeth, making the teeth smoother,
increasing the reflection of light from the surface of the teeth
and thereby giving the teeth a brighter, more lustrous appearance
and whiter visual effect. Furthermore, the remineralization process
provides for improved enamel remineralization thus treating and
preventing caries in the oral cavity.
[0041] Accordingly, there is need for improved compositions,
methods and products that overcome the limitations of the prior
art. The challenge remains to create microcapsules and microcapsule
formulations that enhance the mechanical properties of the
composite and wherein the liquid phases within the semi-permeable
microcapsules provide beneficial materials to the composite or
surface to which the composite is attached. Such material,
therefore, include materials for use in a tooth remineralization
technology platform for incorporating stable and effective tissue
remineralization ions that can be incorporated into a myriad of
dental materials and variety of products. Such a delivery platform
would facilitate the formulation of dental products such as any
number of dentifrices capable of remineralization of the teeth.
[0042] The embodiments of the compositions, products and methods,
as described herein, satisfy these and other needs. For purposes of
use with a tooth material, the ultimate impact is an improved
microcapsule having a reduction in recurrent caries, the most
prevalent reason for restoration replacement; whitening of the
teeth; and resulting improvement in overall strength and health of
the teeth in the oral cavity.
SUMMARY OF THE INVENTION
[0043] Compositions, methods, and products that benefit from
improved mechanical properties related to better homogenization of
the continuous and discontinuous phase of a composite, by
functionalizing the surface of a microcapsule which can then
covalently bond with other structures.
[0044] Another aspect of the present invention provides
compositions, products and methods that use microcapsules
comprising a polymerizable functional group therein to enhance the
material properties of the composite, wherein the microcapsules can
be filled with any number of biologic, mechanical, restorative, or
other materials which are suitable for treating the materials which
the composite is attached to. For example, remineralization
materials may include salt ions, which serve to increase bone
mineralization at localized sites or remineralization of teeth
directly in the oral cavity. Such materials, thus, may be utilized
in conjunction with treatments of a wide variety of conditions
where it is desired to increase bone or tissue mass as a result of
any condition which can be improved by bioavailability of
physiological salts, particularly of calcium and phosphate.
[0045] Another aspect of this invention relates to further
improvement of mechanical properties of a composite by the ability
to create novel fillers with unique morphologies and chemical
compositions. Accordingly, embodiments as described herein relate
to the simplification of a manufacturing process that eliminates
the need for additional steps for the surface treatment of fillers.
Accordingly, the embodiments provide for improvements of the
mechanical properties of the composite and it does so in a way that
the filler can be made to carry therapeutic agents that can be
released in a controllable manner.
[0046] In further embodiments, disclosed are compositions and
methods that improve the mechanical properties of a composite or
improve the manufacturing process of fillers used in composites by
use of non-therapeutic fillers. The present invention provides
products that are useful in a number of industries, especially for
oral health care. The present invention provides compositions that
include fillers disposed of within the discontinuous phase, wherein
a particular filler includes liquid filled microcapsules that are
surface functionalized with a polymerizable functional group. These
fillers, when combined with monomers and an initiator allow for the
generation of a composite that has the continuous and discontinuous
phases covalently bonded together. The covalent bonding of the
continuous and discontinuous phases leads to a significant
improvement in mechanical properties of a composite, especially in
the area of fracture mechanics. The composition of this invention
affords for the opportunity of producing bondable bioactive
microcapsules where the microcapsule is filled with a liquid that
contains a therapeutic agent. The composition of this invention not
only provides superior fracture properties by nature of the
covalent bonding between the filler and continuous phase, but it
can provide for improvement of other mechanical properties if the
microcapsule is filled with energy absorbing materials such as
rubbers or silicones.
[0047] Another aspect of the disclosure includes bondable bioactive
microcapsules suitable for industrial products in the dental
materials industry, wherein liquid encapsulated in the bondable
microcapsule contained aqueous salt solutions of a calcium,
phosphate or fluoride containing salt, then incorporation of those
microcapsules in a dental materials product for promoting
remineralization. Furthermore, the liquid encapsulated in the
bondable microcapsule contained aqueous solutions of an
antimicrobial agent, including, but not limited to benzalkonium
chloride or cetylpyridinium chloride then incorporation of those
microcapsules into a dental materials product with antimicrobial
properties would be achieved. Similarly, combinations of
remineralizing and antimicrobial compounds are desirable in certain
embodiments.
[0048] In essence, this invention simultaneously enhances the
mechanical properties and simplifies the manufacturing of a
composite by virtue of having built-in surface functionalization,
while adding the benefit of having the filler be therapeutic or
mechanically toughening depending on its chemical composition.
[0049] Another aspect of the disclosure includes a composition
comprising of a monomer, an initiator, and a microcapsule
encapsulating an aqueous solution of a salt, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer.
[0050] Another aspect of the disclosure includes a composition
comprising of a monomer, an initiator, and a microcapsule
encapsulating an aqueous solution of a salt, specifically calcium,
fluoride or phosphate or combinations thereof, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer.
[0051] Another aspect of the disclosure includes a composition
comprising of a polymeric continuous phase and a microcapsule
encapsulating an aqueous solution of a salt, specifically calcium,
fluoride or phosphate or combinations thereof, wherein said
microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer.
[0052] Another aspect of the disclosure includes a composition
comprising of a polymeric continuous phase and a microcapsule
encapsulating a fluid, wherein said microcapsule has a surface
functionalized with a polymerizable functional group that is
covalently bonded to the continuous phase.
[0053] A further embodiment is directed to a composition comprising
a continuous phase comprising a monomer, and a discontinuous phase
comprising at least one filler comprising a microcapsule
encapsulating a fluid, and an initiator, wherein said microcapsule
has a surface functionalized with a polymerizable functional group
capable of polymerizing with said monomer.
[0054] A further embodiment is directed to a composition comprising
of a monomer, an initiator, and a microcapsule encapsulating an
aqueous solution of a salt selected from the group consisting of:
benzalkonium, cetylpyridinium, and iodide, and combinations
thereof, wherein said microcapsule has a surface functionalized
with a polymerizable functional group capable of polymerizing with
said monomer.
[0055] A further embodiment is directed to a composition comprising
of a TEGMA and bisGMA monomers, an initiator, and a microcapsule
encapsulating an aqueous solution of a salt selected from the group
consisting of: benzalkonium, cetylpyridinium, and iodide, and
combinations thereof, wherein said microcapsule has a surface
functionalized with a polymerizable functional group capable of
polymerizing with said monomer. The microcapsule is between 2-5 w/w
% of the composition and has methacrylate functional groups on the
surface, wherein the methacrylate group reacts with the
methacrylate groups of the monomers in the continuous phase.
[0056] Another aspect of the disclosure provides a method for
manufacturing a composition having a microcapsule and a continuous
phase, wherein said microcapsule comprises a functionalized surface
capable of covalently bonding to the continuous phase comprising:
mixing an oligomeric urethane by reaction of a diol and
diisocyanate, in which the diisocyanate is used in molar excess,
and reacting for a about 1 hour; adding 2-hydroxyethylmethacrylate
to the resulting oligomeric urethane mixture to terminate chain
ends with methacrylate functional groups; isolating the
functionalized urethane; adding the isolated functionalized
urethane to an oil phase comprising an emulsifying agent and an
organic solvent wherein a surfactant free inverse emulsion is
formed with the addition of an aqueous phase that may contain a
salt; adding diol to the surfactant free reverse emulsion to
polymerize the urethane oligomers and encapsulate the aqueous
solution; and isolating the microcapsules by centrifugation.
[0057] Another aspect of the disclosure provides a method for
manufacturing a composition having a microcapsule and a continuous
phase, wherein said microcapsule comprises a functionalized surface
capable of covalently bonding to the continuous phase comprising:
synthesizing oligomeric or polymeric material with functional
groups capable of reacting with monomers of a continuous phase;
isolating the functionalized oligomeric or polymeric material;
adding the isolated functionalized material to an oil phase
comprising an emulsifying agent and an organic solvent wherein a
surfactant free inverse emulsion is formed with the addition of an
aqueous phase that may contain a salt; adding chain extender to the
surfactant free reverse emulsion to increase the molecular weight
of the functionalized oligomeric or polymeric material and
encapsulate the aqueous solution; and isolating the functionalized
microcapsules by centrifugation.
[0058] Another aspect of the invention is a method of use any one
of the compositions to impart additional structural features into a
polymer or composite material.
BRIEF DESCRIPTION OF THE DRAWINGS
[0059] FIG. 1 is a drawing of a flow-chart showing the preparation
of an embodiment of a surface functionalized microcapsule.
[0060] FIG. 2 depicts a liquid filled microcapsule having a polymer
exterior and a liquid center, which is in contact with the polymer
and attached a functional group.
[0061] FIG. 3 depicts a liquid filled microcapsule and ions
disposed of therein.
[0062] FIG. 4 depicts a bondable microcapsule positioned in a
mixture of monomers, wherein two different monomers are
depicted.
[0063] FIG. 5 depicts a bondable microcapsule wherein the
functional group attached to the microcapsule is covalently bonded
to a polymer.
[0064] FIG. 6 depicts two microcapsules bonded to a now polymerized
group of monomers.
[0065] FIG. 7 depicts two possible urethane microcapsules having
different functional groups that can react with HEMA to form
several different functional microcapsules.
[0066] FIG. 8 depicts the methacrylate terminated polyurethane from
FIG. 7 and a monomer which are then covalently bonded in the bottom
structure.
DETAILED DESCRIPTION OF THE INVENTION
[0067] The embodiments of the invention and the various features
and advantages thereto are more fully explained with references to
the non-limiting embodiments and examples that are described and
set forth in the following descriptions of those examples.
Descriptions of well-known components and techniques may be omitted
to avoid obscuring the invention. The examples used herein are
intended merely to facilitate an understanding of ways in which the
invention may be practiced and to further enable those skilled in
the art to practice the invention. Accordingly, the examples and
embodiments set forth herein should not be construed as limiting
the scope of the invention, which is defined by the claims.
[0068] As used herein, terms such as "a," "an," and "the" include
singular and plural referents unless the context clearly demands
otherwise.
[0069] As used herein, the term "about" means within 10% of a
stated number.
[0070] There exists a broad need for improved microcapsule
compositions and methods useful for therapeutic agent delivery. In
particular, there is a need for an improved microcapsule-based
technology for delivering therapeutic agents to diverse tissue
types in a stable and time-controlled manner.
[0071] Microcapsules have other uses in far ranging fields based on
the chemical structure and properties of the microcapsules. For
example, it may be advantageous to use microcapsules and
compositions comprising such microcapsules with plastics, gels,
pastes, adhesives, paint products, and generally with products that
utilize polymers of any sort. Indeed, such improvements may lead to
uses in industries unrelated to health and oral health such as in
manufacturing, aeronautics, plastic manufacturing, and similar
fields.
[0072] One aspect of this invention addresses the challenge of
incorporating fillers into continuous phases. Compositions, methods
and products that benefit from improved mechanical properties
related to better homogenization of the continuous and
discontinuous phase of a composite is addressed in this invention.
Another aspect of this invention relates to further improvement of
mechanical properties of a composite by the ability to create novel
fillers with unique morphologies and chemical compositions. This
invention relates to the simplification of a manufacturing process
that eliminates the need for additional steps for the surface
treatment of fillers. This invention not only improves the
mechanical properties of the composite, it does so in a way that
the filler can be made to carry therapeutic agents that can be
released in a controllable manner.
[0073] Composites are ubiquitous in structural materials. Typically
a polymeric continuous phase is mixed with discontinuous filler or
fillers. The mixing of the filler into the continuous phase is done
with the purpose of enhancing some property of the composite that
could otherwise not be achieved by the continuous phase alone. A
significant challenge that remains in the development of composite
materials is the discontinuity that is created between the
continuous phase and the filler. This discontinuity provides a
pathway for crack propagation through the composite that results in
mechanical properties that are not optimal, and at times
prohibitive of using a particular continuous/filler combination
that would otherwise have been suitable for a target
application.
[0074] In order to address the mechanical issues created by the
introduction of the filler into the continuous phase, additional
manufacturing steps are typically required. For example, in the
field of dental materials, a variety of glass fillers are used to
improve the performance of the composite. However, the glass
fillers, if used untreated, provide a facile pathway for crack
propagation in the material. In order to address this issue, glass
fillers are subjected to an additional manufacturing step. Prior to
inclusion into a dental formulation, the glass fillers are
silanated. The silanation process provides a surface treatment that
allows the glass filler to form a covalent bond to the continuous
phase. The covalent linkage between the filler and the continuous
phase eliminates the facile pathway for crack propagation. In order
for the crack to propagate through the composite with the surface
treated filler, significantly more energy is required, thereby
enhancing the fracture mechanics of the composite (e.g. fracture
toughness is increased).
[0075] Other examples of surface treatment exist to create a better
bonding surface in composites. One such example is corona, or
plasma treatment. Many plastics, such as polyethylene and
polypropylene, have chemically inert and nonporous surfaces with
low surface tensions causing them to be non-receptive to bonding
with printing inks, coatings, and adhesives. Although results are
invisible to the naked eye, surface treating modifies surfaces to
improve adhesion. However, due to the non-covalent nature of the
surface treatment, plasma treatment typically becomes less
effective over time.
[0076] The present application provides for improved or simplified
manufacturing methods of organic or hybrid based fillers used in
composite materials. The method of microcapsule synthesis
eliminates the need for additional manufacturing steps typically
required for the effective incorporation of discontinuous fillers
into composite materials. Many composite based products are
envisioned from this invention, including composite based
formulations of sealants, cements, glazes, varnishes and many other
dental and non-dental based materials.
[0077] Compositions, methods and products that benefit from
improved mechanical properties related to better homogenization of
the continuous and discontinuous phase of a composite. This is
achieved by functionalizing the exterior surface of microcapsules
such that the microcapsules can covalently bond with the continuous
phase. Accordingly, the continuous phase and the discontinuous
phase are covalently bonded upon initiation or reaction of the
materials. This approach can generally be accomplished by preparing
microcapsules that have a polymeric shell. This polymeric shell can
be synthesized with functional groups off the back bone or side
chain of the polymer that can subsequently undergo chemical
reactions with other functional groups present in the monomer or
polymer of a continuous phase resulting in a bond between the
microcapsule and the continuous phase.
[0078] Accordingly, the present disclosure describes improvements
in microcapsules, their formulation, and compositions, compounds,
and methods for the mineralization of various physiological
tissues, including mineralized connective tissues, primarily of
bone and teeth using such microcapsules. Mineralized connective
tissue or tissues include teeth, bone, and various connective
tissues such as collagen, cartilage, tendons, ligaments and other
dense connective tissue and reticular fibers (that contains type
III collagen) of a mammal, including a human being. For purposes of
definition in this specification, "mineralized tissue" shall mean
bone and teeth specifically. Each of the terms "mineralization" and
"tissue mineralization" are used interchangeably herein and mean a
process in which crystals of calcium phosphate are produced by
bone-forming cells or tooth-forming cells and laid down in precise
amounts within the fibrous matrix or scaffolding of the mineralized
tissue as defined hereinabove.
[0079] Calcium phosphates are a class of minerals containing, but
not limited to, calcium ions together with orthophosphates,
metaphosphates and/or pyrophosphates that may or may not contain
hydrogen or hydroxide ions.
[0080] For purposes of definition in this specification,
"remineralization" is the process of restoring minerals, in the
form of mineral ions, to the hydroxyapatite latticework structure
of a tooth. As used herein, the term "remineralization" includes
mineralization, calcification, re-calcification and fluoridation as
well as other processes by which various particular ions are
mineralized to the tooth. The term "teeth" or "tooth" as used
herein includes the dentin, enamel, pulp and cementum of a tooth
within the oral cavity of an animal, including a human being.
[0081] In certain embodiments, the present invention provides
methods for remineralization surface of a tooth material by using
the microcapsules formulations, as described herein, containing one
or more materials disposed of therein which are suitable for being
released from the microcapsule for remineralizing a tooth material
or bone surface. For purposes of definition in this specification,
as referred to herein, a "tooth material" refers to natural teeth,
dentures, dental plates, fillings, caps, crowns, bridges, dental
implants, and the like, and any other hard surfaced dental
prosthesis either permanently or temporarily fixed to a tooth
within the oral cavity of an animal, including a human being.
[0082] Another aspect of this invention relates to further
improvement of mechanical properties of a composite by the ability
to create novel fillers with unique morphologies and chemical
compositions. Accordingly, this invention relates to the
simplification of a manufacturing process that eliminates the need
for additional steps for the surface treatment of fillers. This
invention not only improves the mechanical properties of the
composite, it does so in a way that the filler can be made to carry
therapeutic agents that can be released in a controllable
manner.
[0083] The present invention presents compositions and methods that
improve the mechanical properties of a composite or improve the
manufacturing process of fillers used in composites. The present
invention provides products that are useful in a number of
industries, especially for oral health care. The present invention
provides compositions that include fillers, especially liquid
filled microcapsules that are surface functionalized with a
polymerizable functional group. These fillers, when combined with
monomers and an initiator allow for the generation of a composite
that has the continuous and discontinuous phases covalently bonded
together. The covalent bonding of the continuous and discontinuous
phases leads to a significant improvement in mechanical properties
of a composite, especially in the area of fracture mechanics.
[0084] The composition of this invention affords for the
opportunity of producing bondable bioactive microcapsules if the
filler is a microcapsule filled with a liquid that contains a
therapeutic agent. The composition of this invention not only
provides superior fracture properties by nature of the covalent
bonding between the filler and continuous phase, but it can provide
for improvement of other mechanical properties if the microcapsule
is filled with energy absorbing materials such as rubbers or
silicones. Indeed, several fillers can be utilized to produce a
variety of microcapsules, which can then be combined together. In
particular embodiments it is particularly suitable to mix one of
more of a variety of microcapsules to provide a composition with
certain physical and chemical properties, whereby the release of
different materials from the different microcapsules provides
advantageous effects. Accordingly, antimicrobial, remineralizing,
and physical property enhancing microcapsules can be admixed alone,
on in combinations thereof. Other suitable filler components
include detergents, dyes, abrasives, flavors, and other components
known to one of skill in the art that are suitable for filling in a
microcapsule.
[0085] The bondable bioactive microcapsules are suitable for
industrial products in the dental materials industry. If the liquid
encapsulated in the bondable microcapsule contained aqueous salt
solutions of a calcium, phosphate or fluoride containing salt, then
incorporation of those microcapsules in a dental materials product
for promoting remineralization would be desirable. If the liquid
encapsulated in the bondable microcapsule contained aqueous
solutions of an antimicrobial agent such as benzalkonium chloride
or cetylpyridinium chloride then incorporation of those
microcapsules into a dental materials product with antimicrobial
properties would be achieved.
[0086] In essence, this invention simultaneously enhances the
mechanical properties and simplifies the manufacturing of a
composite by virtue of having built-in surface functionalization,
while adding the benefit of having the filler be therapeutic or
mechanically toughening depending on its chemical composition.
[0087] This results in a composition comprising of a continuous
phase and a discontinuous phase, wherein in the continuous phase is
provided a monomer and optionally an initiator, and the
discontinuous phase a microcapsule encapsulating a material, for
example, an aqueous solution of a salt, wherein said microcapsule
has a surface functionalized with a polymerizable functional group
capable of polymerizing with said monomer. Indeed, in particular
embodiments, the salt is a calcium, fluoride, or phosphate salt, or
combinations thereof. Other suitable salts may be preferred in
non-dental treatments and are also suitable for use with the
functionalized microcapsules described herein.
[0088] Similarly, the composition can be described as comprising a
polymeric continuous phase, a microcapsule encapsulating a
material, for example, an aqueous solution of a salt, specifically
calcium, fluoride or phosphate or a combination thereof, wherein
said microcapsule has a surface functionalized with a polymerizable
functional group capable of polymerizing with said monomer.
[0089] Indeed, in particular embodiments, the composition comprises
a polymeric continuous phase, a microcapsule encapsulating a fluid,
wherein said microcapsule has a surface functionalized with a
polymerizable functional group that is covalently bonded to the
continuous phase.
[0090] A particularly suitable composition for pit and fissure
sealant with remineralization capabilities and enhanced fracture
toughness is described as follows. A pit and fissure sealant
containing resin, glass fillers, microcapsules with acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate, microcapsules with acrylate functionalized
surfaces that contain a 6 M aqueous solution of potassium phosphate
dibasic, and microcapsules with acrylate functionalized surfaces
that contain an aqueous solution of sodium fluoride, and at least
one photoinitiator.
[0091] Photoinitiators used in the compositions and materials
described herein are additives that assist in the formation of
polymers from the monomers. In many dental composite materials the
photoinitiator is soluble in the continuous phase. Activation of
the photoinitiator is performed by providing a light source,
typically a high energy light source in the visible spectrum, which
activates the initiator to initiate the polymerization process.
However, suitable photoinitiators may also be in the discontinuous
phase in the embodiments described herein. Other initiators may
also be suitable based on the circumstances of use as is known to
one of ordinary skill in the art.
[0092] In other compositions, a composition for pit and fissure
sealant with antimicrobial properties and enhanced fracture
toughness is described as follows. A pit and fissure sealant
containing resin, glass fillers, microcapsules with acrylate
functionalized surfaces that contain a 5 w/w % aqueous solution of
benzalkonium chloride (5 w/w %), and photoinitiators (1 wt %).
[0093] In other compositions, a composite material with enhanced
mechanical properties is described as follows. A resin mixture (16
wt % total) was first made by combining UDMA resin with TEGDMA
resin in a 4/1 ratio. A photosensitizer (camphoroquinone) was added
at 0.7 wt % of the total composition. An accelerator
(ethyl-4-dimethylaminobenzoate) was added at 0.25 wt % of the total
composition. An inhibitor (4-methoxyphenol) was added at 0.05 wt %
of the total composition. The resin, photosensitizer, accelerator
and inhibitor were combined in a flask and mixed at 50.degree. C.
Upon homogenization, the above resin blend was mixed with the
following fillers (84 wt % total): silanated strontium glass 71 wt
%, fumed silica 10 wt %, microcapsules with acrylate functionalized
surfaces that contain high molecular weight silicone oil 3wt %.
Such composition can be used in any number of fields as described
herein.
[0094] A method for the production of surface functionalized
microcapsule filled with encapsulated aqueous remineralizing agents
is described. An oligomeric urethane is synthesized by the reaction
of a diol and a diisocyanate. The diisocyanate is used in a molar
excess. After 1 hour of reaction between the diol and diisocyanate,
oligomeric urethane is achieved. At this point
2-hydroxyethylmethacrylate is added to the synthesis medium of the
urethane in order to terminate a percentage of the chain ends with
methacrylate functional groups. The methacrylate functionalized
urethane is isolated and added to an oil phase that contains an
emulsifying agent. This solution is mixed and a surfactant free,
inverse emulsion is formed as an aqueous solution containing sodium
fluoride salt is added. After half an hour, diol is added to the
surfactant free, inverse emulsion to effectively polymerize the
urethane oligomers and encapsulate the aqueous solution. The
microcapsules are isolated by centrifugation. The microcapsules
have surface methacrylate functional groups that readily polymerize
with other methacrylate monomers of a continuous phase.
[0095] In view of the polymers utilized, the microcapsules are
non-biodegradable, and thus materials contained therein are
released from the microcapsules via diffusion. This provides a
different profile than biodegradable polymers or other polymers
that are intended to burst, releasing the entire contents of the
capsule at once.
[0096] In certain embodiments, the surface of the microcapsule is
effectively functionalized with a vinyl group to allow the vinyl
groups to covalently bond with the monomer in the continuous phase.
The preparation of the vinyl group is performed through a three
step process.
Step 1: Preparation of Surface Functionalized Shell Material:
##STR00001##
[0097] Step 2: Preparation of Surface Functionalized
Microcapsule
[0098] Mix surface functionalized shell material, emulsifying
agent, oil phase. Agitate mixture, with or without heat. Add an
aqueous phase or other liquid phase (silicon). Perform an
interfacial polymerization of the urethane in the surfactant free
inverse emulsion. Isolate surface functionalized microcapsules.
Step 3: Formulation of Surface Functionalized Microcapsule
[0099] Combine surface functionalized microcapsule with desired
continuous phase monomers and initiator. The surface functional
group should be polymerizable with the monomer to create a covalent
link between the filler and continuous phase.
[0100] In a preferred embodiment, a microcapsule is formed using
polyurethane that has a fraction of the polyurethane methacrylate
terminated. This forms a non-biodegradable capsule that is
semi-permeable to therapeutic agents such as calcium ions, fluoride
ions, phosphate ions, benzalkonium cations or cetyl pyridinium
cations which can diffuse through the microcapsule membrane.
Furthermore, through reaction of the methacrylate on the surface of
the non-biodegradable microcapsule can then react with methacrylate
in the continuous phase, which forms a carbon-carbon bond. The
carbon-carbon covalent bond increases the fracture toughness of the
composite material by bonding the microcapsule to the continuous
phase, as depicted in FIGS. 5, 6, and 8B.
[0101] FIG. 1, provides a representative flow-chart for preparation
of a surface functionalized shell material wherein the surface of
such shell is functionalized to allow for covalent bonding between
the microcapsule and the continuous phase. As described in Step 1,
a chemical process results in vinyl terminated components
functionalized to the shell of the microcapsule. Following in Step
2, the surface functionalized shell materials are combined with an
emulsifying agent and an oil phase. The mixture is agitated with or
without heat before an aqueous phase or other liquid phase, such as
silicone, is added. An interfacial polymerization of the urethane
in a surfactant free inverse emulsion. The surface functionalized
microcapsules can then be isolated as appropriate.
[0102] In Step 3, the functionalized microcapsules are combined
with the desired continuous phase monomers and initiators. The
surface functional groups on the microcapsules are polymerizable
with the monomer to create covalent bonds between the filler and
the continuous phase. This provides that the functionalized
microcapsules are then covalently bonded to the continuous
phase.
[0103] Many classes of polymers can be utilized in the scope of the
invention and the choice depends on the specific desired
properties. Examples include, but are not limited to
non-biodegradable iterations of the following classes: acrylic
polymers, alkyd resins, aminoplasts, coumarone-indene resins, epoxy
resins, fluoropolymers, phenolic resins, polyacetals,
polyacetylenes, polyacrylics, polyalkylenes, polyalkenylenes,
polyalkynylenes, polyamic acids, polyamides, polyamines,
polyanhydrides, polyarylenealkenylenes, polyarylenealkylenes,
polyarylenes, polyazomethines, polybenzimidazoles,
polybenzothiazoles, polybenzoxazinones, polybenzoxazoles,
polybenzyls, polycarbodiimides, polycarbonates, polycarboranes,
polycarbosilanes, polycyanurates, polydienes,
polyester-polyurethanes, polyesters, polyetheretherketones,
polyether-polyurethanes, polyethers, polyhydrazides,
polyimidazoles, polyimides, polyimines, polyisocyanurates,
polyketones, polyolefins, polyoxadiazoles, polyoxides,
polyoxyalkylenes, polyoxyarylenes, polyoxymethylenes,
polyoxyphenylenes, polyphenyls, polyphosphazenes, polypyrroles,
polypyrrones, polyquinolines, polyquinoxalines, plysilanes,
polysilazanes, polysiloxanes, polysilsesquioxanes, polysulfides,
polysulfonamides, polysulfones, polythiazoles, polythioalkylenes,
polythioarylenes, polythioethers, polythiomethylenes,
polythiophenylenes, polyureas, polyurethanes, polyvinyl acetals,
polyvinyl butyrals, polyvinyl formals. One skilled in the art will
further appreciate that the selection of the specific type of
polymer will impact the composition and permeability
characteristics of the microcapsules of the invention and that
certain polymers are more applicable to certain industrial
applications as compared to applications in the field or
dentistry.
[0104] In addition to the various possible polymers suitable for
microcapsule formation, suitable polymerizable functional groups
may also be used. Embodiments as disclosed herein utilize a bond
between a functionalized microcapsule and a monomer. In preferred
embodiments, a covalent bond is utilized, however, those of skill
in the art will recognize than any number of suitable bonding
mechanisms may be appropriate based on the chemistries
utilized.
[0105] In preferred embodiments, the number of functional groups
extending from a single microcapsule is between about 1% and 33% of
all positions possible on the polyurethane microcapsule. However,
further preferred embodiments include between about 0.1% and 99.9%
of all possible positions, and preferably between about 1% and 50%,
about 1% and 25%, about 1% and 10%, about 1% and 5%, and about 1%
to about 3%.
[0106] The amount of functional groups can be modified as known to
one of ordinary skill in the art, wherein the number of functional
groups therefore can modify the properties of the ultimate polymer
material formed through combination of the microcapsule and the
monomers. In dental materials encapsulating calcium, fluoride, and
phosphate, preferred amounts are between about 1% and 25%, and more
preferably between about 1% and 5%.
[0107] Indeed, FIG. 2 provides a sample of a liquid filled
microcapsule 10, having the liquid phase 11 in contact with the
polymer shell, and the functional group 12 attached thereto.
[0108] FIG. 3 provides further detail that representative ions, in
this case Na+ 16 and F- 15 are each present in the liquid phase
within the microcapsule. As is known to one of ordinary skill in
the art, all anions (including fluoride) must have accompanying
cations. The sodium and fluoride here are depicted ionically to
depict that they are dissolved in water. Thereafter, through
diffusion, the ions can exit the microcapsule, as depicted through
lines 13 and 14.
[0109] The semi-permeable nature of the non-biodegradable polymer
allows for diffusion of the materials contained therein. Diffusion
rates can be modified based on several factors as known to one of
ordinary skill in the art. The variables that control the diffusion
rate include, but are not limited to the initial concentration of
the ions in solution in the microcapsule, the chemical composition
of the microcapsule, and the w/w loading of the microcapsules in
the continuous phase.
[0110] FIG. 4 provides a depiction of a bondable microcapsule which
is a hydroxyethylmethacrylate functionalized microcapsule 10, which
is positioned in a mixture of monomers, in this case, a first
monomer triethylene glycol dimethacrylate 30 and a second monomer
bisphenol A glycerolate dimethacrylate 40. These components can
then react to allow the functional group on the microcapsule 10 to
bond to the monomers 30 or 40 as depicted in FIG. 5, which shows a
number of "m" microcapsules in the polymeric structure 50 dependent
on how many repeat units are present.
[0111] Indeed, FIG. 5 is essentially a close-up of a microcapsule
at the molecular level, whereas FIG. 6 provides an example of two
microcapsules 10 bonded (whereas 20 is a bond between the polymer
50 and the microcapsule) within a polymer 50 at a macro level. In
FIG. 5, R 22 and R' 21 can be a hydrogen or any functional group.
Furthermore, the polymer 50 can include any number of n, m, and o
repeating units. Indeed, in a composite material, once formed, the
number of microcapsules within the material is solely dependent on
the density and concentration of the microcapsules in the material.
Ultimately, the surface functionalized microcapsule can be combined
with the desired continuous phase monomers and initiator to react.
The surface functional group should be polymerizable with the
monomer to create a covalent bond between the filler (microcapsule)
and the continuous phase monomer.
[0112] FIG. 7 depicts 2 possible chemical structures 80 and 82 of
the shell materials end groups. In two of the potential structures,
the shell material can have isocyanate functional groups capable of
reacting with HEMA 84. This results in 3 potential shell materials
with methacrylate end groups 86, 88 and 90. One structure can have
a hydroxyl end group and a methacrylate end group, one structure
can have an isocyanate end group and a methacrylate end group and
one structure could have potentially two methacrylate end groups.
Accordingly, these make a functionalized shell for the microcapsule
10 which can be bonded as depicted in FIG. 8.
[0113] FIG. 8 further depicts that the functionalized microcapsule
10 can then combine with a monomer 30. A polyurethane terminated
with at least one methacrylate group 71 can react with a monomer
such as triethylene glycol dimethacrylate 30 during a
polymerization. In this reaction, the carbon-carbon pi bonds 72 add
together in a series of addition reaction to generate a polymeric
structure where the methacrylate group 71 is bonded to the monomer
30, thus binding the microcapsule 10 to the monomer. In FIG. 8 and
as described herein, this can be accomplished by a radical reaction
in which the methacrylate functional group of the microcapsule adds
to a growing polymer chain or network.
[0114] In other embodiments, a composition having functionalized
microcapsules is suitable for admixing into one of any known paint
products. In the aspect of paint, adding functionalized
microcapsules to the body of paint, provides additional strength
and structure to the paint product and increase the strength of the
paint. For example, such a paint may further resist tearing or
peeling as compared to currently available products.
[0115] Similarly, in use in the plastic industry, functionalized
microcapsules can impart additional strength while maintaining
elasticity or flexibility of a product. Alternatively, in other
uses, additional rigidity can be imparted, simply depending on the
components within the functionalized microcapsules.
[0116] Certainly, such microcapsules can be further utilized in
adhesive products, wherein the properties of an adhesive can be
manipulated based on the component of a functionalized microcapsule
such that the adhesive has greater lateral or shear strength, or
has increased flexibility while maintaining a bond. Similarly,
other characteristics can be envisioned based on the component of
the functionalized microcapsule.
[0117] Finally, it the use of such functionalized microcapsules can
be facilitated into one of any number of polymer based products.
This allows for modification and improvement of any number of
materials, including wearable fabrics, ballistic products, solid
and rigid products, etc. However, by using the functionalized
microcapsules, the character of the polymer can be amended based on
the need and ultimate use of the product.
[0118] Accordingly, the compositions and materials that can be
encapsulated into the various microcapsules are far ranging. These
include restorative ions, such as calcium, phosphate, and fluoride,
anti-bacterial components such as benzalkonium or cetylpyridinium
ions, but may also include other materials. Additional compositions
may include other suitable ionic materials, antibacterial
materials, whitening materials, and the like. However, in other
classes of use, such as in industrial uses, microcapsules may
contain other materials to enhance the physical properties of the
materials. For example, rubber materials, silicone materials, or
other similar natural or synthetic material or polymers that
provide for different structural properties. Suitable silicone
materials include, but are not limited to those having a molecular
weight between about 12,500 and 2,500,000 g/mol.
[0119] The use of an inhibitor may be suitable in certain
embodiments as a material to prevent autopolymerization in the
material.
[0120] Accelerator and photosensitizer are frequently used together
in photoinitiator chemistry to initiate the polymerization of the
material and to accelerate the polymerization. Therefore, the
material can be polymerized quickly in certain circumstances, such
as when making a dental composite in the mouth.
[0121] These components can therefore be imparted into solid,
liquid, gels, aerosols and the like. By imparting pre-determined
characteristics to the functionalized microcapsules, it is possible
to impart pre-determined functionality to such a product.
EXAMPLES
Example 1
Composition of Matter Example 1a (Sealant A, 2 wt % Bondable
Microcapsule)
[0122] A composition for pit and fissure sealant with
remineralization capabilities and enhanced fracture toughness is
described as follows. A pit and fissure sealant containing resin
(67 wt %), glass fillers (30 wt %), microcapsules with acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate (2 wt %), and photoinitiators (1 wt %).
Composition of Matter Example 1b (Sealant B, 2 wt % Non-Bondable
Microcapsule)
[0123] A composition for pit and fissure sealant with
remineralization capabilities and enhanced fracture toughness is
described as follows. A pit and fissure sealant containing resin
(67 wt %), glass fillers (30 wt %), microcapsules without acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate (2 wt %), and photoinitiators (1 wt %).
Composition of Matter Example 1c (Sealant C, 5 wt % Bondable
Microcapsule)
[0124] A composition for pit and fissure sealant with
remineralization capabilities and enhanced fracture toughness is
described as follows. A pit and fissure sealant containing resin
(64 wt %), glass fillers (30 wt %), microcapsules with acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate (5 wt %), and photoinitiators (1 wt %).
Composition of Matter Example 1d (Sealant D, 5 wt % Non-Bondable
Microcapsule)
[0125] A composition for pit and fissure sealant with
remineralization capabilities and enhanced fracture toughness is
described as follows. A pit and fissure sealant containing resin
(64 wt %), glass fillers (30 wt %), microcapsules without acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate (5 wt %), and photoinitiators (1 wt %).
[0126] Table 1: The fracture toughness for the 4 sealant
formulations that contain non-bondable microcapsules as controls
and the new bondable microcapsules.
TABLE-US-00001 Sample Average Fracture Toughness, (K.sub.IC) 2 w/w
% non-bondable 1.2 .+-. 0.2 microcapsules, control 2 w/w % bondable
microcapsules 2.0 .+-. 0.4 5 w/w % non-bondable 1.3 .+-. 0.3
microcapsules, control 5 w/w % bondable microcapsules 2.0 .+-.
0.3
[0127] Accordingly, by addition of bondable microcapsules, the
average fracture toughness increases by more than 50% as compared
to an equivalent weight % control with non-bondable
microcapsules.
Composition of Matter Example 2 (A Plurality of Bondable
Microcapsules Containing Different Therapeutic Agents in the Same
Formulation)
[0128] A composition for pit and fissure sealant with
remineralization capabilities and enhanced fracture toughness is
described as follows. A pit and fissure sealant containing resin
(64 wt %), glass fillers (30 wt %), microcapsules with acrylate
functionalized surfaces that contain a 5 M aqueous solution of
calcium nitrate (2 wt %), microcapsules with acrylate
functionalized surfaces that contain a 6 M aqueous solution of
potassium phosphate dibasic (1 wt %), microcapsules with acrylate
functionalized surfaces that contain a 0.8 M aqueous solution of
sodium fluoride (2 wt %), and photoinitiators (1 wt %).
Composition of Matter Example 3
[0129] A composition for pit and fissure sealant with antimicrobial
properties and enhanced fracture toughness is described as follows.
A pit and fissure sealant containing resin (64 wt %), glass fillers
(30 wt %), microcapsules with acrylate functionalized surfaces that
contain a 5 w/w % aqueous solution of benzalkonium chloride (5 w/w
%), and photoinitiators (1 wt %).
Composition of Matter Example 4
[0130] A composition for a dental resin composite with enhanced
mechanical properties is described as follows. A resin mixture (16
wt % total) was first made by combining UDMA resin with TEGDMA
resin in a 4/1 ratio. A photosensitizer (camphoroquinone) was added
at 0.7 wt % of the total composition. An accelerator
(ethyl-4-dimethylaminobenzoate) was added at 0.25 wt % of the total
composition. The photosensitizer and accelerator are commonly used
together in photoinitiator chemistry. An inhibitor
(4-methoxyphenol) was added at 0.05 wt % of the total composition.
The resin, photosensitizer, accelerator and inhibitor were combined
in a flask and mixed at 50.degree. C. Upon homogenization, the
above resin blend was mixed with the following fillers (84 wt %
total): silanated strontium glass 71 wt %, fumed silica 10 wt %,
microcapsules with acrylate functionalized surfaces that contain
high molecular weight silicone oil 3wt %.
Example 5
[0131] A composition for a flexible denture base material with
enhanced mechanical properties is described as follows. A resin
mixture (16 wt % total) was first made by combining UDMA resin with
TEGDMA resin in a 4/1 ratio. A photosensitizer (camphoroquinone)
was added at 0.7 wt % of the total composition. An accelerator
(ethyl-4-dimethylaminobenzoate) was added at 0.25 wt % of the total
composition. An inhibitor (4-methoxyphenol) was added at 0.05 wt %
of the total composition. The resin, photosensitizer, accelerator
and inhibitor were combined in a flask and mixed at 50.degree. C.
Upon homogenization, the above resin blend was mixed with the
following fillers (30 wt % total): silanated strontium glass 22 wt
%, fumed silica 3 wt %, microcapsules with acrylate functionalized
surfaces that contain high molecular weight silicone oil 5 wt
%.
[0132] Although the present invention has been described in
considerable detail, those skilled in the art will appreciate that
numerous changes and modifications may be made to the embodiments
and preferred embodiments of the invention and that such changes
and modifications may be made without departing from the spirit of
the invention. It is therefore intended that the appended claims
cover all equivalent variations as fall within the scope of the
invention.
* * * * *